GALLBLADDER MUCOSAL FUNCTION AND CHOLELITHIASIS

这一项目的长期目标是确定该病的发病机制 含钙胆结石(GS)的治疗和开发安全、有效的方法 用于他们的预防和治疗。我们认为所有的GS都应该被考虑 作为胆固醇(Xol)和钙质结节的光谱。在…的一端 光谱是所谓的“纯”Xol宝石(它含有可见光 胆红素钙在其中心区域)。另一端是黑色的 (胆红素钙)色素结石。中间是“混合”的石头 含有可变的木酚和钙盐，由钙离子反应形成 胆汁中对钙敏感的4种阴离子中的一种或多种： 胆红素、碳酸盐、磷酸盐和游离脂肪酸。钙 因此，胆汁中的沉淀显然是印心过程中必须发生的事件。 以及所有色素结石的生长。此外，由于所有的Xol宝石 在它们的中央病灶区域含有钙，我们和其他人有 推测钙沉淀物可能是成核的核心 是Xol的。根据这一观点，钙在人体健康中起着至关重要的作用 各种类型GS的形成及胆结石的进一步阐明 形成需要阐明那些导致钙的因素。 在胆汁中沉淀。在财团任职期间，取得了很大进展 阐明了钙在胆汁中溶解的热力学。 在动态区，我们发现胆汁中含有有效的抑制因子 碳酸钙结晶。两个特别重要的发现是：(1)钙离子 离子在对流H2O通量中被动地进入胆小管 参与犬肝脏胆盐(BS)分泌和(2)游离钙离子 和胆汁是由Gibbs-Donnan力控制的，由 腔内非本意的阴离子胆盐。因此，游离钙离子将永远 存在于胆汁中，并可能治疗降低[Ca~(2+)] 预防和治疗GS必须通过腔内完成 络合作用。因此，人们进行了广泛的研究，以开发一种钙离子- 螯合BS，已经取得了很大进展；进一步的研究是 建议。在这项提案中，我们要解决的问题是，为什么 动物模型，似乎是在粘蛋白凝胶中形成的，而不是在块状 胆汁相。在这方面，我们提出的重要意见 在严重肥胖的患者中，他们容易发生以下GS 胃旁路手术是：(1)[粘蛋白]和游离(钙)都是 显著增加的GB胆汁，和(2)即使(钙)是 增加，实际上低于BS诱导的Gibbs的预测- 唐南部队。为了解释这一点，我们提出了一个“库仑捕鼠器”。 该假说取决于两个因素：(1)相对较厚的粘蛋白凝胶， 和(2)由国标局分泌的H+离子使凝胶部分质子化 上皮(通过Na+/H+交换)。

The long-term goal of this project is to define the pathogenesis of calcium-containing gallstones (GS) and to develop safe, effective methods for their prevention and treatment. We believe all GS should be considered as a spectrum of cholesterol (XOL) and calcium concretions. At one end of the spectrum are so-called "pure" XOL stones (which contain visible calcium bilirubinate in their central regions). At the other end are black (calcium bilirubinate) pigment stones. In-between are "mixed" stones containing variable XOL and calcium salts, formed by reaction of Ca2+ ions with one or more of the 4 "calcium-sensitive" anions of bile: bilirubinate, carbonate, phosphate, and free fatty acids. Calcium precipitation in bile is thus a clear requisite event in the initiation and growth of all pigment stones. In addition, since all XOL stones contain calcium in their central nidus regions, we and others have postulated that calcium precipitates may serve as a nidus for nucleation of XOL. According to this view, calcium plays a crucial role in the formation of all types of GS, and further elucidation of gallstone formation requires elucidation of those factors which lead to calcium precipitation in bile. During tenure of the Consortium, great progress has been made in elucidating the thermodynamics of calcium solubility in bile. In the kinetic area, we have found that bile contains potent inhibitors of CaCO3 crystallization. Two particularly important findings were: (1) Ca2+ ions enter bile passively at the canaliculus in the convective H2O flux attending bile salt (BS) secretion, and (2) free [Ca2+] in canine hepatic and gallbladder (GB) bile is governed by Gibbs-Donnan forces induced by intraluminal, impermeant, anionic bile salts. Thus, free Ca2+ will always be present in bile and possible therapeutic reduction of [Ca2+] for prevention and treatment of GS must be accomplished by intraluminal chelation. Extensive studies have therefore been made to develop a Ca2+- chelating BS, and much progress has been made; further studies are proposed. In this proposal we address the question as to why GS, in all animal models, appear to form in the mucin gel, as opposed to the bulk phase of bile. In this regard, important observations which we have made in patients with severe obesity, who are prone to develop GS following gastric-bypass surgery, are that: (1) Both [Mucin] and free (Ca2+] are significantly increased in GB bile, and (2) Even though (Ca2+] is increased, it is actually lower than that predicted by BS-induced Gibbs- Donnan forces. To explain this, we advance a "Coulombic mousetrap" hypothesis which depends on two factors: (1) A relatively thick mucin gel, and (2) Partial protonation of the gel by H+ ions secreted by the GB epithelium (by Na+/H+ exchange).